Clopidogrel derivatives

In the first step, (R)-2-chlorobenzaldehyde cyanohydrin is prepared by the almond meal-catalyzed addition of HCN to 2-chlorobenzaldehyde. The cyanohydrin is then transformed into the corresponding 2-hydroxy ester by Pinner reaction. Subsequently, the hydroxy group is activated by sulfonylafion and reacted with tetrahydrothieno[3.2-c]pyridine to give, under complete inversion of configuration, the (5 ) — a-amino acid derivative CLOPIDOGREL. ... 

In these synthesis, the optically active (R)-cyanohydrin is transformed into the corresponding a-hydroxy carboxylic ester and the hydroxyl funchon is achvated by sulfonylahon. The treatment of the corresponding intermediate with tetra-hydrothieno[3,2-c]pyridine stereoselectively yields the (S)-configured clopidogrel (Scheme 10.23). In the second case, a mutant of the recombinant almond (Pmnus amigdalus) (R)-oxynitrilase isoenzyme 5 catalyzes the formation of enantiopure (R)-2-hydroxy-4-phenylbutyronitrile [54]. Reaction of the sulfonylated hydroxyester derivative with the corresponding dipeptide leads to the formation of enalapril or lisinopril (Scheme 10.24). 

Pharmacology Clopidogrel is a thienopyridine derivative, chemically related to ticlopidine, that inhibits platelet aggregation. It acts by irreversibly modifying the platelet ADP receptor. Conseguently, platelets exposed to clopidogrel are affected for the remainder of their lifespan. 

Metabolism/Excretion - Clopidogrel is extensively metabolized by the liver. It undergoes rapid hydrolysis into its carboxylic acid derivative glucuronidation also occurs. 

One Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) utilized optically pure (R)-(2-chloro-phenyl)-hydroxy-acetic acid (20), a mandelic acid derivative, available from a chiral pool. After formation of methyl ester 21, tosylation of (/ )-21 using toluene sulfonyl chloride led to a-tolenesulfonate ester 22. Subsequently, the Sn2 displacement of 22 with thieno[3,2-c]pyridine (8) then constructed (-i-)-clopidogrel (2). Another Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) took advantage of resolution of racemic a-amino acid 23 to access (S)-23. The methyl ester 24 was prepared by treatment of (S)-23 with thionyl chloride and methanol. Subsequent Sn2 displacement of (2-thienyl)-ethyl para-toluene-sulfonate (25) assembled amine 26. 

Sankyo Co. Ltd. Tokyo, Japan) is a new thienopyridine derivative that produces more potent platelet inhibition, and a rapid onset of action. The latter properties may provide a superior alternative to clopidogrel, with less response variability and a decreased prevalence of nonresponsiveness (I I I). 

Together with clopidogrel, various other thiophenes are currently used as medicinal drugs. In the following, only a few derivatives are highlighted. 

Clopidogrel is also a thienopyridine derivative which is also more effective than aspirin for the prevention of ischaemic stroke, MI or vascular death in patients at high risk but it is not associated with neutropenia. It is more expensive than aspirin though safer than ticlodipine. 

Ticlopidine is a thienopyridine derivative with potent antiplatelet activity associated with inhibition of ADP-induced platelet aggregation. It was first used in Europe in 1978 in the secondary prevention of stroke and coronary events, the treatment of peripheral vascular disease, and after vascular stent placement. However, the use of ticlopidine has been progressively restricted in some countries because of its serious adverse effects. It has largely been superseded by clopidogrel. 

Clopidogrel bisulphate and aspirin The method was based on the second-derivative spectra of both ingredients. The amplitude at 254.0 nm was used for clopidogrel bisulphate, while at 216.0 nm for aspirin. The linearity was obeyed in the range 5.0- 30.0 pg mL-i for both compounds. 34... 

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